This proposal uses mouse and human studies to explore the role of advanced glycation end products (AGEs) and their receptors in the susceptibility, development and progression of cardiovascular complications in diabetes. Based on exciting preliminary data, we will utilize unique models of accelerated atherosclerosis associated with diabetes to better understand the role of AGEs and their receptors. We will employ state-of-the-art molecular biological and analytical biochemical approaches to assess specific AGEs and AGEs in a number of different experimental models and assess the impact of novel therapies that inhibit the accumulation of AGEs in vivo as well as assessing the effects of known end-organ protective therapies (e.g. agents which interrupt the renin angiotensin system). Key to this proposal, findings in experimental studies will also be tested in clinical studies of patients with type 1 diabetes. In particular, the potential role of AGEs and their receptors will be tested in large prospective cohorts from three different countries, looking specifically at the links between AGEs and established markers of cardiovascular disease. In addition, we will examine the genetic determinants of AGEs and their receptors in patients with type 1 diabetes, and interactions with environmental factors that lead to the development and progression of cardiovascular complications. Finally, we will test for the first time the potential utility of alagebrium chloride, an AGE crosslink breaker, in the management of patients with type 1 diabetes. This outstanding multinational team of experimental biologists, biochemists, clinicians and geneticists represents a unique collaboration, with a specific focus on AGEs and cardiovascular disease. It is anticipated that this series of studies will not only define more accurately the link between various components of the AGE pathway and diabetic vascular complications but will either strengthen the evidence to consider strategies to interrupt current targets or identify new targets for the prevention, treatment and reversal of vascular complications in type 1 diabetes. LAY SUMMARY: Patients with type 1 diabetes are at increased risk of heart attack, stroke and amputation, but how a high sugar causes these complications is not established. Using unique genetic models and patient populations, this study examines the damaging effects of AGEs, formed by the reaction between proteins, fats and glucose, to determine their role in vascular disease in type 1 diabetes. It is anticipated that these studies will ultimately lead to better strategies to treat and prevent diabetic vascular complications.